This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

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Physiology and Pathophysiology of Purinergic Neurotransmission

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

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Cellular distribution and functions of P2 receptor subtypes in different systems.

Parathyroid hormone (PTH) secretion is reg-ulated by a cell surface Ca 2 1 receptor that detects small changesin the level of plasma Ca 2 1 . Because this G protein-coupledreceptor conceivably provides a distinct molecular target fordrugs useful in treating bone and mineral-related disorders, wesought to design small organic molecules that act on the Ca 2 1 receptor. We discovered that certain phenylalkylamine com-pounds, typified by NPS R-568 and its deschloro derivative NPSR-467, increased the concentration of cytoplasmic Ca 2 1 ([Ca 2 1 ] i ) in bovine parathyroid cells and inhibited PTH secre-tion at nanomolar concentrations. These effects were stereose-lective and the R enantiomers were 10- to 100-fold more potentthan the S enantiomers. NPS R-568 potentiated the effects ofextracellular Ca 2 1 on [Ca 2 1 ] i and PTH secretion but waswithout effect in the absence of extracellular Ca 2 1 . Both com-pounds shifted the concentration–response curves for extracel-lular Ca 2 1 to the left. Presumably, these compounds act aspositive allosteric modulators to increase the sensitivity of theCa

Calcimimetics with potent and selective activity on the parathyroid calcium receptor (cytoplasmic Ca21yhyperparathyroidismyparathyroid cellsyNPS R-568yNPS R-467)

The safety of chitosan as a pharmaceutical excipient.

Air Pollution and Cardiovascular Injury: Epidemiology, Toxicology, and Mechanisms

Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer's disease.

Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders.

Determinatin of captopril in biological fluids by gas-liquid chromatography

The antiinflammatory effect of an ointment containing propolis extract (3%-7%) was examined using carrageenan-induced hind paw edema in rats. Treatment with the ointment inhibited the edema moderately, and the inhibition was significant at 5% and 7%. Additionally, the effect of the ointment on chemotaxis of human polymorphonuclear leukocytes (PMNs) was investigated using the agarose plate method. Migration of PMNs toward zymosan-treated serum was inhibited in the presence of 5% propolis ointment. These results demonstrate that topical application of propolis extract is effective in inhibiting carrageenan-induced rat hind paw edema, and its inhibitory effect on the chemotaxis of PMNs may also contribute to the antiinflammatory effect.

Antiinflammatory effect of topically applied propolis extract in carrageenan-induced rat hind paw edema.

Rapeseed oil ingestion and exacerbation of hypertension-related conditions in stroke prone spontaneously hypertensive rats

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease of unknown pathogenesis. Vascular remodeling due to excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a critical pathogenic event that leads to early morbidity and mortality. The excessive cell proliferation is closely linked to the augmented Ca2+ signaling in PASMCs. More recently, we have shown by an siRNA knockdown method that the Ca2+-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, involved in the enhanced Ca2+ response and subsequent excessive cell proliferation. In this study, we examined whether pharmacological blockade of CaSR attenuated the excessive proliferation of PASMCs from IPAH patients by MTT assay. The proliferation rate of PASMCs from IPAH patients was much higher (~1.5-fold) than that of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Treatment with NPS2143, an antagonist of CaSR or calcilytic, clearly suppressed the cell proliferation in a concentration-dependent manner (IC50 = 2.64 μM) in IPAH-PASMCs, but not in normal and CTEPH PASMCs. Another calcilytic, Calhex 231, which is structurally unrelated to NPS2143, also concentration-dependently inhibited the excessive proliferation of IPAH-PASMCs (IC50 = 1.89 μM). In contrast, R568, an activator of CaSR or calcimimetic, significantly facilitated the proliferation of IPAH-PASMCs (EC50 = 0.33 μM). Similar results were obtained by BrdU incorporation assay. These results reveal that the excessive PASMC proliferation was modulated by pharmacological tools of CaSR, showing us that calcilytics are useful for a novel therapeutic approach for pulmonary arterial hypertension.

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Naoki Ohara

Papers

Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders.

Determinatin of captopril in biological fluids by gas-liquid chromatography

Antiinflammatory effect of topically applied propolis extract in carrageenan-induced rat hind paw edema.

Rapeseed oil ingestion and exacerbation of hypertension-related conditions in stroke prone spontaneously hypertensive rats

Inhibition of Excessive Cell Proliferation by Calcilytics in Idiopathic Pulmonary Arterial Hypertension